Using a Dermal Skin Substitute in the Treatment of Chronic Wounds Secondary to Recessive Dystrophic Epidermolysis Bullosa: A Case Series

    The term Epidermolysis bullosa (EB) has been used since 1886 to identify a form of hereditary blistering disease and today is commonly used to describe a family of genetic disorders that cause blistering and shearing of the skin from even the mildest trauma.

    The disease manifests in several different forms that vary considerably in their severity and symptoms.¹ In some forms, the blistering is localized to hands and/or the feet; in others, the whole body can be affected. Blistering also may occur internally (eg, in the mouth or esophagus), giving rise to other complications.² Many common everyday practices can cause skin damage in people with EB.

    One in 227 people in the general population has a defective gene that may result in EB.³ An estimated two out of every 100,000 Americans⁴ have some form of EB. In Canada, an estimated 300 to 1,000 people suffer from this disease⁵ and in the UK approximately 5,000 people are living with the disease, most of whom are children.⁶ Not all babies born with severe EB survive the first year; those who do have constant blistering, which causes scarring that constricts the skin of the hands and feet. They can become disfigured and the fingers and toes can fuse together, often requiring reconstructive surgery.^7,8

    Epidermolysis bullosa affects both sexes and all racial groups. One in 17,000 live births worldwide produces an infant with a form of EB.⁴ In 1986, a national registry was established in the US to track the number of people with EB. This registry contains almost 3,300 persons documented with EB⁴ but this number is believed to underestimate the true incidence.

Classification

    Epidermolysis bullosa can be divided into three main types on the basis of the location of the defect above, within, or below the basement membrane. Location of the defect is also a major determinant for patient symptoms. Each of the main types can be subdivided into several variants. Currently, 27 clinical variations and disorders in six adhesion molecules are known.⁹ The main types are EB Simplex, Junctional EB, Dystrophic EB, and Recessive Dystrophic EB.

    Epidermolysis bullosa simplex is characterized by separation of the skin above the basement membrane in the basal epidermal layer. Junctional EB is differentiated by the separation of the skin through the basement membrane. Dystrophic EB is identified by the separation of the skin below the basement membrane zone. Recessive Dystrophic EB (RDEB) presents at birth with bullae and fragile skin. Patients with RDEB can develop numerous traumatic erosions and blisters at any time. Atrophic scarring can include fusing of the fingers and toes to form pseudo-webbing and club-like digits. The abnormality may relate to structurally abnormal type VII collagen, leading to a separation of the epidermis from the dermis at the level of anchoring filaments. Approximately 70% of people with EB suffer from EB simplex, 10% from Junctional EB, and 20% from the dystrophic variant.²

Clinical Management

    Epidermolysis bullosa can range from a relatively mild condition to a severely disabling and sometimes fatal disease. It involves many physiological systems, requiring parents and caregivers to develop a team approach when treating the EB patient.^10,11 Intense and total patient care often must be provided, particularly for young and growing children.

    Patients with milder forms may have periods of temporary disability but can lead relatively normal lives. In more severe forms, EB can be emotionally and physically devastating, causing disability and deformity. The severe forms require intensive nursing care similar to that given to burn patients¹²; this care is often provided by the child’s parents. In all cases, EB treatment is largely symptom-directed and supportive.¹³ Care should focus on preventing infection, protecting the skin against trauma, attending to nutritional deficiencies and dietary complications, minimizing deformities and contractures, and providing psychological support for the entire family.¹³ Educating all individuals (eg, primary care physician, dermatologist, nurse, dentist, gastrointestinal specialist, nutritionist, plastic surgeon, psychologist, social worker, teachers, relatives, baby sitters, and many others) who come in contact with the patient is essential. Proper care and family support can greatly enhance the quality of life for EB patients.

    Common care challenges. Patients with EB frequently experience painful blisters and open sores.¹⁴ When necessary, the patient’s healthcare provider may prescribe brief courses of appropriate analgesics for pain relief. Itching is a sign of inflammation or secondary infection. Systemic antihistamines may be helpful but should be used only with the approval of a physician.

    Scarring rarely occurs in patients with EB simplex, is common in persons affected with Junctional or Dystrophic EB, and is most severe in individuals who have RDEB.¹⁵

    Repeated friction and trauma on hands and feet cause blistering; in the more severe forms of EB, these blisters heal, causing scarring and side-to-side fusing or webbing together of fingers and toes (syndactyly). Contractures (shortening of the skin) of the hands and feet also may contribute to loss of function. Flexion contractures can occur on joints in the feet, knees, and hips. Muscle atrophy (weakening) develops as a result of disuse of a joint. Scarring may decrease the mouth opening (microstomia) and may limit tongue movement (ankyloglossia).

    To date, research has not found a cure or single treatment to control any form of EB but gene therapy may be able to correct the defect.^16-20 However, many complications can be lessened or avoided through early intervention and optimized care.²¹

    Interventions. The Dystrophic Epidermolysis Bullosa Research Association (DEBRA) provides a variety of recommendations and care suggestions for patients and their families, including:^4,22
   • Use non-adhesive dressings only
   • Use cautious hand manipulation and exercise to maintain hand movement
   • Use splints to reduce chance of contractures
   • Consult with a physiotherapist or occupational therapist. They are helpful in creating programs of activity that optimize hand function.

    If hand function is impaired, consulting with a plastic or other surgeon with an interest in hand surgery is advised. The surgeon will determine if surgery is necessary or waiting is the better option. The surgical procedure involves separating the fused digits and releasing contractures while the patient is under anesthesia. Skin grafts or various bioengineered skin products may be used to cover wounds, avoiding difficult-to-heal donor sites. Hand splints are used to help keep fingers separated and to keep hands in an extended position postsurgically. Careful instructions for post care should be given by the surgeon. Healing usually takes several weeks to months; for this reason, usually only one hand is done at a time.

    The child with EB should be encouraged to be as active as possible. Physical or occupational therapy is beneficial and will usually improve function.

Skin Care and Wound Healing

    The importance of good skin and wound care cannot be overemphasized. Due to the nature of EB, blistering and open wounds compromise the integrity of the skin, which is the first line of defense against infection. As soon as a break in the continuity of skin occurs, the healing regimen should be initiated.

    Skin and periwound management. Good skin care and bandaging²³ are performed to reduce the incidence of infection, assist healing of involved areas, and provide a protective cushioning against friction.
Clinicians treating EB should understand that wounds are in various stages of healing and may require different treatments to optimize the wound bed for healing.²⁴ For instance, wounds with minimal drainage may require additional moisture to enhance healing. Some wounds may drain heavily and require more absorptive dressings or an increase in the dressing change frequency to help manage drainage. Each wound is unique with its own set of circumstances. Keeping that in mind may help when choosing wound products to optimize healing.

    Analgesia, as ordered by the caregiver, may be offered before dressing changes for comfort. Daily cleansing may include a bath with mild soap or cleansers. However, these local skin and wound care procedures are maintenance procedures — they do not primarily promote wound healing.

    Opening the blisters may relieve pain and help healing.²³ However, after the blister is drained, the blister roof should be left intact and covered with a sterile non-adherent dressing. Any open area on the skin or mucous membranes is a potential site for infection.²⁵ The best way to prevent infection is to keep the area clean. An antimicrobial dressing may be used to decrease bacterial burden.

    Pruritus (itchy skin) may be caused by inflammation due to infection, chronic wounds, and the healing process.²⁶ Scratching the area will further damage the wound bed. Systemic sedation using antihistamine syrups at night and on an as-needed basis in the daytime are often useful to control itch.

    Factors such as poor nutritional intake, possible malabsorption of nutrients, and anemia can contribute to poor wound healing.²⁷ Because patients with EB may have swallowing problems due to esophageal lesions, they often are tube-fed. Monitoring the nutritional status with regard to body weight, albumin, and other parameters is critical.

    Wound healing. In chronic wounds, the orderly sequence of repair (inflammatory, proliferative, re-epithelialization, and remodeling stages) is disrupted. The chronic wound must be directed back to this orderly nexus of events. The changing paradigm for local wound care must address three factors: debridement, wound-friendly moist interactive dressings (moisture balance), and bacterial balance.

    Winter^28,29 and Ginsburg³⁰ demonstrated the benefits of moist interactive healing but clinical practices have not always kept pace with the evidence base. Clinical evidence and judgment are important components of selecting a suitable moist wound dressing (see Table 1).³¹ To date, few if any dressings will complete all the outlined requirements.³²

    Despite treating the cause, providing appropriate local wound care (debridement, bacterial balance, and moist interactive healing), and attending to patient-centered concerns, a certain percentage of wounds do not heal with best practices.

    However, a new and expanding cadre of biological agents offers hope for some of the most difficult wounds (see Figure 1).^33,34

Tissue Engineering

    One approach to the treatment of chronic wounds in EB is tissue engineering, where cells similar to those of the skin are grown on a three-dimensional scaffold and used to induce healing. These skin substitutes lack antigen-presenting cells, potentially improving take and subsequent healing.

    Among the first tissue-engineered commercially available products are those used to treat patients who have damaged or destroyed skin (eg, burns or chronic ulcers). One example is a human-based bioengineered dermal substitute (Dermagraft™, Smith & Nephew, Largo, Fla.) (see Figure 2). This skin substitute is comprised of human dermal fibroblasts taken from the foreskin of newborns following routine circumcision.³⁵ The fibroblasts are cultured onto a bioabsorbable, polygalactin mesh, which serves as a three-dimensional scaffold.³⁶ During tissue formation, the fibroblasts proliferate and secrete human dermal collagen, matrix proteins, and growth factors. The fibroblasts are protected by a cryoprotectant during the freeze process so they are viable when applied to the skin.

    The skin substitute is intended to stimulate and aid the wound healing process³⁷ by delivering a living human dermal matrix to the debrided wound bed. Metabolically active fibroblasts have been shown to retain the capacity to secrete a variety of growth factors and matrix proteins.³⁸ The collagen and glycosaminoglycans are similar in distribution and ultrastructural arrangement to healthy skin. In in vitro studies, the product expresses several growth factor genes, including PDGFA chain, TGF-b1, TGFb3 and VEG F, which promote cell proliferation, matrix deposition, and angiogenesis — all of which encourage wound healing.³⁷

    This dermal skin substitute was developed initially as a treatment for diabetic foot ulcers. When implanted, the product replaces the patient’s compromised dermal bed and allows for the patient’s own epithelial cells to migrate and heal the wound. Clinical studies have shown that it is a safe and effective treatment that results in faster healing of full-thickness diabetic neuropathic foot ulcers when compared to current standards of care.^39-41

    Currently, this product is licensed in Canada for the management of difficult-to-heal chronic wounds. In the UK, it is licensed for the management of full-thickness, non-healing, diabetic neurotrophic foot ulcers, and hard-to-heal venous leg ulcers only. In the US, the product is licensed for use in diabetic (neurotrophic) foot ulcers and EB (Humanitarian Device Exemption).

Methodology

    After completing an exploratory pilot study evaluating the dermal skin substitute in the treatment of difficult-to-heal wounds, the authors started using the product in patients with EB who had difficult-to-heal wounds to assess the potential for the skin substitute to help these wounds heal and improve patient/family quality of life. If healing was not possible, the product at least might temporarily relieve and manage pain.

    Evaluation design. A retrospective chart review was conducted to evaluate the results of using this product in patients with RDEB. Standard procedures included adequate preparation of the wound bed before dressing application. Each patient was treated with a number of pieces of the product; frequency of application was based on clinical need. The patients were followed as part of regular clinical practice.

    Inclusion/exclusion criteria. Patients had to have persistent chronic wounds of at least 1 month’s duration with no progression to healing and RDEB, willing to have the skin substitute applied, and able (both patient and caregiver) to comply with the follow-up regimen. Patients who were pregnant or planning to become pregnant as well as those with a history of poor adherence/compliance with medical treatment or follow-up could not participate. Patients (or their caregivers) who were unable to understand the purpose and objectives of this evaluation and follow-up of treatment also were excluded.

    Procedure. Based on multiple case reports documenting variable successes with skin substitutes in the treatment of different types of EB^42,43 where significant benefit was observed, the human fibroblast-derived dermal substitute was applied to web spaces and digits following surgical release of hand deformities in four patients and to areas with persistent erosions secondary to RDEB to six patients. In all cases, the product was secured in place with sutures or small adhesive strips (Steristrips™, 3M, St. Paul, Minn.) or silicone tape and covered with a secondary dressing. On all postoperative and some eroded areas, an ionized, nanocrystalline silver-coated dressing was applied over the skin substitute in an attempt to promote and maintain bacterial balance. Non-adhesive or silicone-backed foam dressings (Mepilex™, Mölnlycke Health Care, Newtown, Pa.) were used for moisture balance. Patients were reassessed, where possible, at 1, 2, and 8 weeks; clinicians visually evaluated epidermal coverage, noting complete wound coverage and absence of surface moisture. All treated wounds were followed up for an initial period of 8 weeks, with long-term follow-up over an extended period. Clinical outcomes were summarized in the form of case histories.

    Outpatient product application procedure and follow up. All procedures were carried out in a clinic or office site. No anesthesia was necessary (see Figure 3). Implant sites were pre-treated with nanocrystalline silver dressing (Acticoat, Smith & Nephew, Largo, Fla.) for 2 weeks. Wounds were debrided as little as possible; generally, no debridement was needed. Wound site tracings were used to size and cut the dermal substitute.

    Before implantation, the skin substitute was thawed, rinsed, and prepared according to manufacturer directions. The product was cut up to 1 cm greater than the wound size at the physician’s discretion. From the clinics’ previous experience with this product, an overlap technique was developed (not in accordance with the current product labeling) that involved extending the product beyond the epidermal margin to help prevent friction and shearing and to protect or immobilize the cells. The overlapping portion of the product dehydrates and adheres to the wound margin, providing a seal and immobilizing the product.

    The product was placed into the wound bed and smoothed gently so the sheet was in contact with the entire wound surface and the wound margin (either side of the sheet can be face down on the wound). The edges were secured with silicone tape or small adhesive strips.

    Follow-up visits were conducted at 1, 2, and 8 weeks and 12 months if possible. The skin substitute was reapplied as needed. Wounds were assessed at each visit; photographs of the wound were taken immediately before the skin substitute was applied. Wound tracings were performed if appropriate. Healing was defined as full epithelialization of the wound with the absence of drainage or surface moisture. The percentage of epithelial coverage was estimated at every visit and averaged (see Table 2). As a general procedure, if at week 4 the wound was not 30% smaller, a re-application of the skin substitute was considered. The product permanently integrates with the wound bed and subsequent applications are implanted in layers into the wound on top of previously applied product. Wound dressings to address bacterial and moisture balance (eg, a soft silicone dressing and gauze retention bandage) were applied during the skin substitute treatment period. If needed, a nanocrystalline dressing was applied under the soft silicone dressing. No tape products were used in order to prevent damage to the fragile skin. No petrolatum gauze or any other glycerin-based products were used over skin substitute sites, as these may affect adhesion.

    Frequency of dressing change was determined on a patient-by-patient basis. Because maintaining a moist wound-healing environment throughout the study was important, dressings were changed as clinically indicated and, based on the clinicians’ previous clinical experience, no dressing changes were required for 72 hours.

    Clinical infection, defined as the presence of the usual clinical signs of infection,⁴⁴ was assessed at each clinical visit. Increased bacterial burden was recognized as the presence of bright red friable granulation tissue with increased exudate and new areas of yellow slough on the wound surface. Where clinical infections or increased surface bacterial burden was present, further skin substitute treatment was withheld until the infection cleared. Many patients received low-dose, anti-inflammatory antibiotics 1 week before skin substitute application. Systemic antibiotics were continued for 1 to 2 weeks after the procedure was completed. Antibiotics such as erythromycin and trimethoprim were chosen for their anti-inflammatory properties and a specific choice was made, where appropriate, based on the sensitivity of organisms obtained from bacterial swabs or quantitative skin biopsy. All patients were instructed to contact the clinician if signs or symptoms of infection developed before the next scheduled visit.

    Patients were instructed to keep their wounds out of the shower or bath; areas around the wound could be washed with mild soap and water, keeping the dressings in place. If the dressings became wet, patients were instructed to follow the dressing change procedure. However, epithelial buds present at 1 week continue to spread and re-epithelialize over time; as a result, it is best to disturb the wound bed as little as possible.